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Ginsenoside Rd Is Efficacious Against Acute Ischemic Stroke by Suppressing Microglial Proteasome-Mediated Inflammation

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Abstract

A great deal of attention has been paid to neuroprotective therapies for cerebral ischemic stroke. Our two recent clinical trials showed that ginsenoside Rd (Rd), a kind of monomeric compound extracted from Chinese herbs, Panax ginseng and Panax notoginseng, was safe and efficacious for the treatment of ischemic stroke. In this study, we conducted a pooled analysis of the data from 199 patients with acute ischemic stroke in the first trial and 390 in the second to reanalyze the efficacy and safety of Rd. Moreover, animal stroke models were carried out to explore the possible molecular mechanisms underlying Rd neuroprotection. The pooled analysis showed that compared with placebo group, Rd could improve patients’ disability as assessed by modified Rankin Scale (mRS) score on day 90 post-stroke and reduce neurologic deficits on day 15 or day 90 post-stroke as assessed by NIH Stroke Scale (NIHSS) and Barthel Index (BI) scores. For neuroprotective mechanisms, administration of Rd 4 h after stroke could inhibit ischemia-induced microglial activation, decrease the expression levels of various proinflammatory cytokines, and suppress nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IκBα) phosphorylation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation. An in vitro proteasome activity assay revealed a significant inhibitory effect of Rd on proteasome activity in microglia. Interestingly, Rd was showed to have less side effects than glucocorticoid. Therefore, our study demonstrated that Rd could safely improve the outcome of patients with ischemic stroke, and this therapeutic effect may result from its capability of suppressing microglial proteasome activity and sequential inflammation.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 31170801 to S.M., No. 81372115 to Z.G.Y., No. 81171236 to L.X.D., and No. 81371365 to Z.G.).

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The authors declare no conflict of interests.

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    Authors and Affiliations

    1. Department of Neurology, Xijing Hospital, The Fourth Military Medical University, 15 Changle-xi Road, Xi’an, 710032, China

      Guangyun Zhang, Feng Xia, Yunxia Zhang, Xiao Zhang, Xuedong Liu, Gang Zhao & Ming Shi

    2. Medical Center of Neurology, The First Affiliated Hospital, Chinese PLA General Hospital, Beijing, China

      Yunxia Zhang

    3. Department of Pediatrics, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, China

      Yuhong Cao

    4. Department of Statistics, The Fourth Military Medical University, Xi’an, Shaanxi, China

      Ling Wang

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    Correspondence to Xuedong Liu, Gang Zhao or Ming Shi.

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    Guangyun Zhang, Feng Xia, and Yunxia Zhang contributed equally to this work.

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    ESM 1

    (DOCX 18 kb)

    Supplementary Figure 1

    Schematic diagrams for experimental procedures of MCAO in rats (A) and cultured microglia subjected to OGD or LPS injury (B). (GIF 21 kb)

    High resolution image (TIFF 253 kb)

    Supplementary Figure 2

    Disposition of patients in the pooled study. (GIF 26 kb)

    High resolution image (TIFF 529 kb)

    Supplementary Figure 3

    Rd inhibits p65 nuclear translocation. Immunofluorescence staining of NF-κB p65 and Hoechst 33342 (Ho) in rat cortical penumbra regions in Sham (A-C), MCAO (D-F), and MCAO+Rd (G-I) groups. Arrows and arrowheads show cytosolic and nuclear location of p65 immunoreactivities, respectively. Scale bar: 10 μm. (GIF 412 kb)

    High resolution image (TIFF 4820 kb)

    Supplemental Table 1

    Baseline characteristics of patients with ischemic stroke included in the full analysis set (FAS) (DOCX 14 kb)

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    Zhang, G., Xia, F., Zhang, Y. et al. Ginsenoside Rd Is Efficacious Against Acute Ischemic Stroke by Suppressing Microglial Proteasome-Mediated Inflammation. Mol Neurobiol 53, 2529–2540 (2016). https://doi.org/10.1007/s12035-015-9261-8

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